Barraud Solenn, Vacher Sophie, Schiffler Camille, Wong Jennifer, Hamza Abderaouf, Courtois Laura, Pinton Antoine, Servant Nicolas, Baulande Sylvain, Attignon Valery, Soubeyran Isabelle, Rouleau Etienne, Coussy Florence, Campone Mario, Legrand François, Jimenez Marta, André Fabrice, Bachelot Thomas, Bièche Ivan
Department of Genetics, Institut Curie, Paris Cité University, Paris, France.
Direction of Clinical Research and Innovation, Léon Bérard Cancer Center, Lyon, France.
Br J Cancer. 2025 Jun 12. doi: 10.1038/s41416-025-03083-5.
Treatment of advanced estrogen receptor-positive HER-2-negative breast cancer is based on hormonal therapy with aromatase inhibitors for postmenopausal women. However, acquired endocrine resistance is unavoidable at some point in the advanced or metastatic stage, and its underlying molecular mechanisms remain to be fully elucidated. The study prospectively included patients with advanced or metastatic breast cancer who had relapsed or progressed following treatment with a non-steroidal aromatase inhibitor (AI) and were treated with exemestane (a steroidal AI) and everolimus. The objective was to perform DNA and RNA analyses in order to gain a deeper understanding of the genomic and transcriptomic landscape of endocrine-resistant advanced BC.
We selected 65 patients included between 2015 and 2018 in the SAFIRTOR trial (NCT02444390). NGS-based gene panel of 65 genes (SAFIR02 core panel), Comparative genomic hybridization array and RNA-sequencing assessed single nucleotide variations, copy-number variations and gene expression and fusion genes of interest, respectively.
The most prevalent genomic alteration was ESR1, observed in 49% (32/65) of cases, with most being activating missense mutations. Two cases of ESR1 fusions were identified. The observed alterations were not mutually exclusive with those from NF1 or ERBB2. Differential expression analysis in the presence or absence of ESR1 alterations showed significant enrichment of the ESR-mediated signaling pathway in tumors with ESR1 alterations (p < 0.005). 17 genes were identified as significantly differentially expressed, forming a transcriptional signature with 81.3% sensitivity and 84.3% specificity (p < 0.0001). The oxidative phosphorylation (OXPHOS) pathway was significantly associated with resistance to everolimus (p = 5.05 × 10). 16 genes were differentially expressed between responders and non-responders, forming a OXPHOS gene signature distinguishing two groups with markedly different outcomes.
晚期雌激素受体阳性、人表皮生长因子受体2阴性乳腺癌的治疗基于对绝经后女性使用芳香化酶抑制剂进行激素治疗。然而，在晚期或转移阶段的某个时间点，获得性内分泌耐药是不可避免的，其潜在分子机制仍有待充分阐明。该研究前瞻性纳入了晚期或转移性乳腺癌患者，这些患者在接受非甾体芳香化酶抑制剂（AI）治疗后复发或进展，并接受了依西美坦（一种甾体AI）和依维莫司治疗。目的是进行DNA和RNA分析，以更深入了解内分泌耐药晚期乳腺癌的基因组和转录组格局。
我们选择了2015年至2018年纳入SAFIRTOR试验（NCT02444390）的65例患者。基于二代测序的65个基因的基因panel（SAFIR02核心panel）、比较基因组杂交阵列和RNA测序分别评估单核苷酸变异、拷贝数变异以及感兴趣的基因表达和融合基因。
最常见的基因组改变是ESR1，在49%（32/65）的病例中观察到，大多数为激活型错义突变。鉴定出2例ESR1融合。观察到的改变与来自NF1或ERBB2的改变并非相互排斥。在存在或不存在ESR1改变的情况下进行差异表达分析显示，ESR1改变的肿瘤中ESR介导的信号通路显著富集（p < 0.005）。鉴定出17个基因有显著差异表达，形成了一个转录特征，灵敏度为81.3%，特异性为84.3%（p < 0.0001）。氧化磷酸化（OXPHOS）途径与对依维莫司的耐药显著相关（p = 5.05 × 10）。16个基因在反应者和无反应者之间差异表达，形成了一个OXPHOS基因特征，区分出两组结局明显不同的患者。
